Most psychiatric disorders are not due to mutations in a single gene but rather involve cellular pathways under control of many genes and molecular signals. Recent studies point to the fact that complex epigenetic mechanisms regulating gene activity 'above'the genetic nucleotide sequence may be involved as well. The best understood mechanism of epigenetic modification is DNA methylation. In this genome-wide study we will examine the role of DNA methylation in schizophrenia susceptibility. Our study consists of a genome-wide discovery and replication phase to identify CpG loci in the human genome that are under epigenetic control and involved in disease susceptibility, followed by locus-specific validation in large schizophrenia cohorts. Our systematic approach for identifying candidate CpG loci involved in disease also includes study of general features of DNA methylation such as age, gender and genetic controls. The genome-wide effort with comparative analyses of multiple brain regions of patients and controls will provide a unique opportunity to establish what role DNA methylation plays in vulnerability to develop schizophrenia and perhaps other psychiatric traits. Public Health Relevance: Biochemical modifications of DNA and chromosome structure provide heritable information that is not encoded in the DNA sequence itself, but is likely to play a role in disease susceptibility. We will screen the human genome of schizophrenia patients and unaffected control subjects in order to identify these sites involved in disease. This will lead to a better understanding of the genetic basis of schizophrenia.